In pulmonary arterial hypertension, the pulmonary vasculature undergoes significant remodeling. The immediate aftermath of this is that normal gaseous exchange with the external environment cannot take place.
“PAH, including idiopathic PAH, is characterized by a progressive rise in pulmonary vascular resistance and occlusive vascular remodeling, which leads to right heart failure and premature death,” Evans and colleagues wrote in the European Respiratory Journal.
Naeije and colleagues wrote that PAH was a “rare dyspnoea-fatigue syndrome due to a progressive increase in pulmonary vascular resistance (PVR) and eventual right ventricular (RV) failure.”
In both these definitions, which are remarkably similar in essence, it is important to note that vascular remodeling and the subsequent increase in pulmonary vascular resistance result in the phenotypes characteristic of PAH.
Read more about PAH etiology
In this article, we will explore a few theories on how pulmonary vasculature breaks down in PAH.
Effects of Lifestyle Habits
To better understand the faulty mechanisms underlying PAH pathophysiology, it is worth revisiting the work of scientists on understanding how lung mechanics, ventilation, and gas exchange operate in the context of PAH.
Studies using lung function tests of patients with PAH demonstrated that there is only a mild decrease, if any at all, in the diffusing capacities of the lung for carbon dioxide (DLCO). However, if the study group was widened to include patients who were smokers or had existing cardiorespiratory comorbidities, a more significant decrease in DLCO became observable in contemporary PAH registries.
In simple terms, existing comorbidities, smoking, and older age can pathologically interfere with existing lung dynamics and increase the likelihood of pathological vasculature malformation.
A Closer Look at the Right Ventricle
“Right ventricular function adaptation to increased afterload in PAH relies on increased contractility to match increased arterial elastance,” Naeije and colleagues wrote. “RV-arterial coupling in PAH is decreased during exercise and either preserved or decreased at rest. RV-arterial uncoupling eventually results in RV dilation, increased RV filling pressures and clinically manifest right heart failure. RV-arterial coupling is of prognostic relevance.”
Put simply, the behavior of the right ventricle can trigger a series of steps that result in right heart failure. A higher load increases contractility of the heart muscles, which requires right ventricular function to adapt. RV-arterial coupling in PAH, when under significant stress, can eventually lead to right heart failure.
“Since RV function is the major determinant of symptoms and outcome in PAH, simple noninvasive methods for its evaluation are being developed,” the authors of the study wrote.
One such device is the ratio of tricuspid annular plane systolic excursion (TAPSE). One of the key measurements from this device is the validated TAPSE/sPAP [systolic pulmonary pressure] ratio, which can serve to predict prognosis in patients with heart failure and PAH.
“Endothelial cells (ECs) are damaged and/or dysfunctional in PAH patients. Factors that can cause EC injury include hypoxia, toxins, inhibition of survival signaling (e.g. VEGF antagonists), recreational drug use, inflammatory cytokines, as well as pathological shear stress and fluid mechanics in the pulmonary circulation raised by left to right shunts in congenital heart disease,” Evans and colleagues wrote.
Read more about PAH prognosis
“However, the physiological basis of PAH goes beyond [right ventricular] dysfunction. Management of PAH patients requires a thorough understanding of the basic physiology of lung mechanics, pulmonary gas exchange, pulmonary vascular function and the coupling of the right heart to the pulmonary circulation,” Naeije and colleagues wrote.
The onus is on research teams to use these investigational technologies wisely to better understand how we can serve patients in PAH in new and profound ways.
Overlooked and Underappreciated: Endothelial Cells
There are a number of complex biochemical reactions that take place in the lungs of a patient with PAH, and one of them is the endothelial signaling cascade that contributes to the initiation and development of PAH.
In normal individuals, a healthy endothelial monolayer lines the inner wall of the blood vessels. The healthy endothelial layer allows fluid, proteins, and blood cells to cross the vessel wall into the parenchymal tissue. This ensures that the vascular tone and integrity are maintained; in addition, endothelial cells secrete anti-inflammatory and anti-thrombotic properties onto the vascular bed.
Nevertheless, the endothelial cell layer can undergo damage.
“Endothelial cells are damaged and/or dysfunctional in PAH patients,” Evans and colleagues wrote. “Factors that can cause [endothelial cell] injury include hypoxia, toxins, inhibition of survival signaling, recreational drug use, inflammatory cytokines, as well as pathological shear stress and fluid mechanics in the pulmonary circulation raised by left to right shunts in congenital heart disease,” Evans and colleagues wrote.
Since we have ample knowledge of how endothelial cells act as a defense mechanism against pathology, their protective role deserves further research. The ability of the disease to penetrate through the defense system gives rise to the many signs and symptoms associated with this disease.
On paper, PAH is deceptively simple to understand: the lung vasculature becomes abnormal, impeding its main task of facilitating respiration. However, as we have seen from the literature review, many other biochemical reactions take place at once, and it would indeed be interesting if PAH pathology can be assessed objectively through a wide lens in the hopes that its pathomechanisms become clear.
Naeije R, Richter MJ, Rubin LJ. The physiological basis of pulmonary arterial hypertension. Eur Respir J. 2022;59(6):2102334 doi:10.1183/13993003.02334-2021
Evans CE, Cober ND, Dai Z, Stewart DJ, Zhao YY. Endothelial cells in the pathogenesis of pulmonary arterial hypertension. Eur Respir J. 2021;58(3):2003957. doi:10.1183/13993003.03957-2020